Ligand-gated ion channels (LGICs) transduce chemical signals into electrical activity by increasing the permeability of neurons to specific ions, resulting in current flow, which alters the propensity of neurons to fire action potentials. Action potentials are rapid fluctuations in neuronal voltage that are used for communicating information in the nervous system. Because many neurological disorders are related to neural activity (e.g. pain and epilepsy), ion channels, including LGICs, have been targeted pharmacologically for clinical therapeutics (Brunton et al. (2006) Goodman & Gilman's The Pharmacological Basis of Therapeutics).
Neuronal activity can be enhanced by administering an agonist for a cation-selective (excitatory) LGIC (e.g. glutamate receptor) or neuronal activity can be suppressed or silenced by administering an agonist for an anion-selective (inhibitory) LGIC (e.g. GABA receptor). In order to modulate neuronal activity of a subset of neurons in the nervous system for a therapeutic effect, these small molecule ligands for LGICs would require targeting by injection, iontophoresis, or reverse dialysis to a volume of the neuropil. However, these techniques are invasive, especially for targets deep in the brain. An even greater limitation is that these perturbations within the targeted brain region are not cell type-specific due to the widespread presence of LGICs (e.g. glutamate and GABA ion channels) on nearly all neurons. Perturbation of neurons that are not involved in the therapeutic effect can lead to significant undesired side effects.
Thus, there is a need in the art to develop LGICs that can be selectively activated with tailored compound ligands. Such novel LGICs, once delivered to the neurons of interest by gene therapy methods, would render these neurons sensitive to a ligand selective for such novel LGICs and would obviate the need for local delivery of the ligand, since the tailored ligand would have no effect on native LGICs. Furthermore, selective activation of these novel LGICs would eliminate the non-specific effects arising from activation of neighboring populations of neurons that inevitably occur due to the ubiquitous expression of native LGICs. This would provide specificity for control of neuron activity that could be used therapeutically to treat diseases such as epilepsy and chronic pain. Also, by manipulating activity of neuron populations that control hunger and satiety, these LGICs and associated ligands could also be used to treat diseases associated with undesired behaviors such as overeating or anorexia. Therefore, development of novel LGICs with unique pharmacology would have therapeutic utility.